2009 senior Scholar Award in aging

New neurons are continuously produced in the adult brain and they may be important for behavior, regeneration, and response to drugs. Production of new neurons continuously declines with age and it is possible that this decline contributes to age-related cognitive impairment. We have recently developed a novel approach to identify and quantify the cellular targets of pro- and anti-neurogenic stimuli and found that age-related decline in hippocampal neurogenesis is driven by the continuous depletion of the neural stem cell pool. Furthermore, we found that the brain employs an unusual strategy to cope with the loss of stem cells - the rate of stem cells' entry into division and their subsequent disappearance drastically decreases with age, such that age-related loss of stem cells is larger than the loss of new neurons. Effectively this means that the ageing brain, while becoming progressively more frugal about using its stem cells, manages to get more "mileage" from the remaining cells and generates more and more neurons from each stem cell as the organism ages. This leads to the somewhat counterintuitive conclusion that the aging brain becomes more, not less, effective in using its pool of stem cells. The main goal of this proposal is to determine the strategies that the brain employs to cope with the decrease in the size of the neural stem cell pool. Towards this goal, we propose to determine how the basic scheme of the division/differentiation control changes with age and to identify molecular players that mediate this control and allow the brain to cope with the age-related loss of stem cells.